title: Lysophosphatidylcholine stimulates MAP kinase activity in rat vascular smooth muscle cells.
abstract: Lysophosphatidylcholine (lyso-PC) has been implicated in atherogenesis and the inflammatory process. Although lyso-PC has been reported to contribute to the mitogenic effect of oxidized LDL on rat cultured vascular smooth muscle cells (VSMCs), the signaling mechanisms by which lyso-PC promotes its proliferation are poorly characterized. Mitogen-activated protein (MAP) kinases are important mediators involved in the intracellular network of interacting proteins that transduces extracellular cues to intracellular responses. We therefore examined the effect of lyso-PC on MAP kinase activation, proto-oncogene expression, and AP-1 binding activity using cultured rat VSMC. Marked activation of MAP kinase occurred within 10 minutes of lyso-PC treatment, whereupon rapid inactivation ensued. MAP kinase activation by lyso-PC was concentration-dependent (6.25 to 25 micromol/L). Pertussis toxin treatment did not affect lyso-PC-induced MAP kinase phosphorylation. Lyso-PC (25 micromol/L) also increased the mRNA expression of c-fos and c-jun genes. An electrophoretic mobility shift assay showed that AP-1 binding activity was enhanced by lyso-PC. To examine the upstream signaling of MAP kinase, we used several inhibitors on MAP kinase activation induced by lyso-PC. Although lyso-PC induced sustained increase in intracellular Ca2+ concentration, EGTA had no effect on MAP kinase activation induced by lyso-PC. However, protein kinase C inhibitor GF109203X and downregulation of protein kinase C activity by prolonged treatment with phorbol ester inhibited lyso-PC-induced MAP kinase activation. These data suggest that lyso-PC transmits its mitogenic activity through a MAP kinase-AP-1 pathway, which exists downstream of its protein kinase C activation in VSMCs.
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: T
authors.initials: T
authors.lastname: Yamakawa
authors.forename: S
authors.initials: S
authors.lastname: Eguchi
authors.forename: Y
authors.initials: Y
authors.lastname: Yamakawa
authors.forename: E D
authors.initials: ED
authors.lastname: Motley
authors.forename: K
authors.initials: K
authors.lastname: Numaguchi
authors.forename: H
authors.initials: H
authors.lastname: Utsunomiya
authors.forename: T
authors.initials: T
authors.lastname: Inagami
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation; D016762:Genes, fos; D016758:Genes, jun; D008244:Lysophosphatidylcholines / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D008244:Lysophosphatidylcholines; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D017871:Calcium-Calmodulin-Dependent Protein Kinases